Cleaning validation citations on 483s, warning letters rising: 40% of API audit 483s had items on cleaning.

Dear Reader,

A pharmaceutical industry consultant, who conducts GMP audits and evaluations of chemistry, manufacturing and controls (CMC), said last month that many of the 483s and warning letters she reviews cite insufficient or lack of cleaning validation as significant problems.

Barbara Unger, consultant with Don Hill & Associates of Silver Spring, MD, urged participants at an International Business Communications conference in San Diego to beef up their cleaning protocols and validation to meet regulatory expectations.

Unger, a former Eli Lilly CMC specialist with 20 years of experience, told the conferees: "Cleaning validation is a 'hot topic' with FDA. In

483 observations and recent warning letters that I've reviewed, in about 40% of those given to API manufacturers there has been at least one item dealing with cleaning." Common deficiencies Unger noted include:

1. Process tanks are routinely reused before cleaning, and no cleaning validation data are available to support this practice.

2. No data exist to support the manual cleaning of centrifuge bowls.

3. Approved cleaning procedures are not specific and are not validatable.

4. Inadequate cleaning of lyophilizer, in that worst-case sampling locations are not identified, and sampling techniques have not been validated.

5. Inadequate production tank cleaning procedures exist. Specifically, validated hold times are not included in the cleaning procedure; cleaning SOPs lack sufficient detail; and no verification of visual inspection for cleanliness.

Unger outlined four areas that regulators expect developers and manufactures to address adequately in their application cleaning plans.

First, the cleaning methodology must be consistent and justified for each piece and type of equipment. It is often best to classify families of equipment, based on criteria such as product contact, equipment construction, internal complexity, length or complexity of piping runs, or the nature of residues. Firms may "make a business case to dedicate certain equipment to certain families of products," Unger said.

She said cleaning protocols must identify what the cleaning process is intended to remove, and how. This includes evaluating the chemical and physical properties of the soils, particularly solubility. Cleaning agents and their concentrations must be identified, as must the temperatures and volumes of rinses and cleaning solutions.

Unger said sampling methods must be specified and validated, including visual examination of cleanliness, rinse solution testing and taking surface swabs.

"The definition of 'clean' must include a definition of 'visually clean,'" she added. Unger also said a manufacturer's plan must also define what a soiled surface looks like. When calculating carryover, cleanliness calculations must cover pediatric (10 kg) dosing, and not just adult (70 kg) dosing. "For multi-product facilities, all soils should be sampled under identical conditions," she added.

Second, facilities must document how critical cleanliness parameters will be controlled. Hard-to-clean areas, such as dip tubes and baffles, must be identified in the equipment and piping designs.

"Don't forget or ignore automation," Unger warned. Automation provides a source of variability, and instrumentation packages running CIP must be evaluated. "Software can say one thing and the equipment can behave in a different manner," she said.

In addition, Unger advised industry to account for cycle times when planning manufacturing capacity and scheduling. "Leave time for adequate cleaning!" she urged.

Unger added that manual operations, which are often hard to control, must specify how cleanliness standards will be maintained, especially among multiple operators.

Third, cleaning protocols must establish and justify "worst case" conditions. "These should include considerations of the equipment and piping configurations, allowable time limits before and after use, and a hierarchy of the relative cleanability of soils," Unger advised.

Finally, Unger reminded the audience that regulators expect that acceptance criteria for cleanliness are practical, achievable and justified. "It's not just a box-checking exercise."

Sincerely, The Editors